meta分析范文展示

Theeffectoffructoseconsumptiononplasmacholesterolinadults:ameta-analysisofcontrolledfeedingtrials1,2,3TaoAn4,5,RongChengZhang4,5,YuHuiZhang4,QiongZhou4,YanHuang4,JianZhang4,*.4StateKeyLaboratoryofCardiovascularDisease,FuwaiHospital,NationalCenterforCardiovascularDiseases,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China5TaoAnandRongChengZhangcontributedequallytothisstudy.3SupplementalTable1andsupplementalFigures1-4areavailableasOnlineSupportingMaterialwiththeonlinepostingofthispaperatRUNNINGTITLE:FructoseandcholesterolWORDCOUNT:5618;NUMBEROFFIGUREA:3;NUMBEROFTABLES:2SUPPLEMENTARYMATERIAL:OnlineSupportingMaterials:5AUTHORLISTFORINDEXING:An,Zhang,Zhang,Zhou,Huang,Zhang1ThestudywassupportedbytheMinistryofScienceandTechnologyofChinawithgrantoftheNationalHigh-techResearchandDevelopmentProgramofChinatoDrJianZhang.2Authordisclosures:T.An,R.C.Zhang,Y.H.Zhang,Q.Zhou,Y.Hung,J.Zhanghavenoconflictsofinterest.*Towhomcorrespondenceshouldbeaddressed.Mailingaddress:HeartFailureCenter,CardiovascularInstituteandFuwaiHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,167Beilishilu,Beijing,China;Zipcode:100000;Telephonenumber:86-10-88396180;Faxnumber:86-10-88396180;E-mail:Fwzhangjian62@163.comPROSPEROREGISTRATIONNUMBERS:CRD42012003351ABSTRACTFructoseiswidelyusedasasweetenerinproductionofmanyfoods,yettherelationbetweenfructoseintakeandcholesterolremainsuncertain.Weperformedasystematicreviewandmeta-analysisofhumancontrolledfeedingtrialsofisocaloricfructoseexchangeforothercarbohydratestoquantifytheeffectsoffructoseontotalcholesterol(TC),LDLcholesterol(LDL-C),andHDLcholesterol(HDL-C)inadulthumans.Weightedmeandifferenceswerecalculatedforchangesfrombaselinecholesterolconcentrationsbyusinggenericinversevariancerandom-effectsmodels.TheHeylandMethodologicalQualitywasusedtoassessstudyquality.Subgroupanalysesandmeta-regressionwereconductedtoexplorepossibleinfluenceofstudycharacteristics.Twenty-fourtrials(withatotalof474subjects)wereincludedinourmeta-analysis.Inanoverallpooledestimate,fructoseexertednoeffectonTC,LDL-CandHDL-C.Meta-regressionanalysisindicatedthatfructosedosewaspositivelycorrelatedwiththeeffectsizesofTCandLDL-C.SubgroupanalysesshowedthatisocaloricfructoseexchangeforcarbohydratescouldsignificantlyincreaseTCby12.97mg/dL(95%CI:4.66,21.29;P=0.002)andLDL-Cby11.59mg/dL(95%CI:4.39,18.78;P=0.002)at>100gfructose/dbuthadnoeffectonTCandLDL-Cwhenfructoseintakewas≤100g/d.Inconclusion,veryhighfructoseintake(>100g/d)couldleadtosignificantlyincreaseinserumLDL-CandTC.Larger,longerandhigher-qualityhumancontrolledfeedingtrialsareneededtoconfirmtheseresults.Keywords:fructose,cholesterol,meta-analysisINTRODUCTIONHyperlipidemiaisacommonriskfactorforcoronaryheartdisease(CHD),with44.4%ofadultsintheUnitedStateshavingabnormalTCvaluesand32%havingelevatedLDL-Clevels(1).Comparedtosubjectswithnormalbloodlipid,thosewithhyperlipidemiahavea3-foldriskofheartattacks(2).LifestylemodificationshouldbeinitiatedinconjunctionbothprimaryandsecondarypreventionofCHD.Moreconsiderationexistsastowhatconstituteshealthyeating.Fructoseisthemostnaturallyoccurringmonosaccharide,andhasbecomeamajorconstituentofourmoderndiet.Fruit,vegetables,andothernaturalsourcesprovidenearlyone-thirdofdietaryfructose,andtwo-thirdscomefrombeveragesandfoodsinthediets(eg,candies,jam,syrups,etc)(3).Fructoseispreferredbymanypeople,especiallythosewithdiabetesmellitusbecauseofitslowglycemicindex(23%versusglucose100%)(4).Afterintestinaluptake,fructoseismainlyremovedfromthebloodstreambytheliverinaninsulin-independentmanner,andisusedforintrahepaticproductionofglucose,fattyacidsorlactate.Cross-sectionalstudiesinhumansuggestthatexcessivefructoseconsumptioncanleadtoadversemetaboliceffects,suchasdyslipidemiaandincreasedvisceraladiposity(5-7).TheDietaryGuidelinesforAmericans,2010,pointoutthatitislackofsufficientevidencetosetatolerableupperintakeofcarbohydratesforadults(8).AlthoughTheCandianDiabetesAssociationsuggestsconsumptionofnomorethan60gofaddedfructoseperdaybypeoplewithdiabetesforitstriglyceride-raisingeffect(9),thethresholddoseoffructoseatwhichtheadverseinfluenceoncholesteroliscontroversial.Todeterminetheeffectoffructoseoncholesterol,asubstantialnumberofclinicaltrialshavebeenperformedonadulthumanswithdifferenthealthstatus(diabetic,obese,overweight,hyperinsulinemic,impairedglucose-tolerantandhealthy).Thesetrialsusedvariousintakelevelsoffructoseanddifferentprotocols.Thus,itisdifficulttoreachaconsistentconclusionacrossthesestudies.Therefore,weconductedasystematicreviewofthescientificliteratureandmeta-analysisofcontrolledfeedingtrialstoevaluatetheeffectofisocaloricoralfructoseexchangeforcarbohydratesoncholesterolandtoclarifytheactivefactorsoffructose.MaterialsandMethodsThismeta-analysisfollowedthePreferredReportingItemsforSystematicReviewsandMeta-analyses(PRISMA)criteria(10).Searchstrategy.WesearchedPubMed(/pubmed;from1966toDecember2012),Embase(;from1966toDecember2012)andtheCochraneLibrarydatabase()byusingthefollowingsearchterms:fructoseand(lipemiaorlipaemiaorlipidsorcholesterolor“totalcholesterol”or“LDLcholesterol”or“HDLcholesterol”)inEnglish.WealsosearchedChinaNationalKnowledgeInfrastructure()andWangfangdatabase()inChineseaccordingtothesearchstrategy.Thesearchwasrestrictedtoreportsoftrialsonhumans.Studyselection.Allclinicaltrialsusingfructoseandindexedwithintheabovedatabaseswerecollected.Twoindependentreviewers(T.A.,R.C.Z)screenedtheabstractsandtitlesforinitialinclusion.Ifthiswasnotsufficient,fulltextsarticleswereobtainedandreviewedbyatleasttwoindependentreviewers(T.A.,R.C.Z,Q.Z.,Y.H.).Thereferencelistsofretrievedarticlesalsousedtosupplementthedatabase.Anydisagreementswereresolvedthroughdiscussion.Weincludedcontrolledfeedingtrialsinvestigatingthechroniceffectoffructoseonbloodcholesterol,frombothrandomizedandnonrandomizedstudies,iftheymetthefollowingcriteria:subjectsmusthavebeenadministeredfructoseforatleast2weeks;studiesinvestigatedtheeffectoforalfree(unbound,monosaccharide)fructosewhencomparedwithisocaloriccontroldietwithanothercarbohydrateinplaceoffructose;studieswereperformedinhumanadultswitheitheraparallelorcrossoverdesign;subjectsinbothexperimentalgroupsandcontrolgroupswereinstructedtoconsumeisocaloricdiets.Ifthestudyreportedanycomparisons,weincludedallsuchcomparisonsinthemeta-analysis.Dataextractionandqualityassessment.Tworeviewers(T.A.,R.C.Z)independentlyextractedrelevantdatafromeligiblestudies.Disagreementswereresolvedbyoneofthetwoauthors(Y.H.Z.,J.Z.).Thesedataincludedinformationonstudyfeatures(author,yearofpublication,studydesign,randomization,blinding,samplesize,comparator,fructoseform,dose,follow-upandmacronutrientprofileofthebackgrounddiet),participantcharacteristics(gender,ageandhealthystatus)andbaselineandfinalconcentrationsornetchangesoftotalcholesterol,LDL-CandHDL-C.Datainitiallyextractedwereconvertedtosysteminternationalunit(eg,TC:1mmol/Lconvertedto38.6mg/dL).Formulti-armstudies,onlyinterventiongroupsthatmetinclusioncriteriawereusedinthisanalysis.Ifbloodlipidconcentrationsweremeasuredseveraltimesatdifferentstagesoftrials,onlyfinalrecordsoflipidconcentrationsattheendofthetrialswereextractedforthismeta-analysis.ThequalityofeachstudywasassessedwiththeHeylandMethodologicalQualityScore(MQS)(11),generalizedasfollows:randomization;analysis;blinding;patientselection;comparabilityofgroupsatbaseline;extentoffollowup;treatmentprotocol;co-intervention;outcomes.Thehighestscoreforeachareawastwopoints.Highernumbersrepresentedabetterquality(MQS≥8).Datasynthesis.StatisticalanalyseswereperformedwithStatasoftware(version11.0;StataCorporation,TX,USA)andREVMANsoftware(version5.2;CochraneCollaboration,Oxford,UnitedKingdom).Separatepooledanalyseswereconductedbyusingthegenericinversevariancerandom-effectsmodelsevenwheretherewasnoevidenceofbetween-studyheterogeneitybecausethesemodelsgivemoreconservativesummaryeffectestimatesinthepresenceofundetectedresidualheterogeneitythanfixed-effectsmodels.Thedifferentchangesfrombaselinebetweenfructoseandcarbohydratecomparatorsfortotalcholesterol,LDLcholesterolandHDLcholesterolwereusedtoestimatetheprincipleeffect.WeappliedpairedanalysestoallcrossovertrialsaccordingtothemethodsofElbourneandcolleagues(12).Weightedmeandifferencesoffructoseconsumptiononcholesterolconcentrationsandcorresponding95%CIswerecalculated.A2-sidedPvalue<0.05wassetasthelevelofsignificanceforaneffect.Thevariancesfornetchangesinserumcholesterolwereonlyreporteddirectlyintwotrials(29,31).Wecalculatenetchangesforotherstudiesbyusingthemeans±SDscholesterolconcentrationsatbaselineandattheendofinterventionperiod(13).SDswerecalculatedfromSEswhentheywerenotdirectlygiven.Ifthesedatawereunavailable,weextrapolatedmissingSDsbyborrowingSDsderivedfromothertrialsinthismeta-analysis(14).Inaddition,weassumedaconservativedegreeofcorrelationof0.5toimputethechange-from-baselineSDs,withsensitivityanalysesperformedacrossarangeofpossiblecorrelationcoefficients(0.25and0.75)(13).Forcrossovertrialsinwhichonlyfinalmeasurementswereincluded,thedifferencesinmeanfinalmeasurementswereassumedonaveragetobethesameasthedifferencesinmeanchangescores(13).Inter-studyheterogeneitywastestedbytheCochrane’sQ-test(P<0.1),andwasquantifiedbytheI2statistic,whereI2≥50%wasevidenceofsubstantialheterogeneity.Toexplorethepotentialeffectsoffactorsontheprimaryoutcomesandinvestigatethepossiblesourcesofheterogeneity,weperformedmeta-regressionsandpredefinedsubgroupanalysesstratifiedbycomparator,dose,studyduration,randomization,healthstatus,studydesignandstudyquality.Asforstudiesusedarangeoffructosedoses,theaveragedosescalculatedonthebasisoftheaveragereportedenergyintakeorweightofparticipants(28.5caloriesperkilogramofbodyweight).SensitivityanalyseswerealsoperformedaccordingtotheCochraneHandbookforSystemicReview.FunnelplotsandEgger’slinearregressiontestwereconductedtodetectpublicationbias.RESULTSBasedonoursearchcriteria,1602eligiblestudieswereidentified,and1565studieswereexcludedonreviewofthetitlesandabstracts.Theremaining37studieswereretrievedandfullyreviewed.Fifteenofthesedidnotmeettheinclusioncriteriaandwereexcludedinthefinalanalysis.Atotalof22studies(providingdatafor24trials)involving474subjects(15-36)wereincludedinthemeta-analysis(SupplementalFig.1,Table1).ThereportsofKohandReiser(22,23)includedtwotrials(bringingthetotalnumberoftrialsto24).Eleventrialswererandomized(17,18,20,21,25,27-29,31,34,36).Nineteentrialsusedcrossover(15-19,21-32),andfiveusedparalleldesigns(20,33-36).Asforthe19cross-overtrials,10trialshavereportedthewashoutperiod(16,18,22,25,27-31),9trialsdidnothavewashoutperiod(15,17,19,21,23,24,26,32).Thetrialsvariedinsize,from8to131subjects.Themeanageoftrialparticipantsrangedfrom26.7to64.4years.Seventeentrials(15,17-23,25,27,28,30,31,34,36)wereperformedinoutpatientsettings,3trials(26,29,32)ininpatientsettings,and4trialsinbothoutpatientandinpatientsettings(16,24,33,35).Ninetrialswereconductedondiabeticsubjects(19-21,24-27,29,30),8trialsinhealthysubjects(17,18,22,23,28,31,34,35),3trialsinoverweight/obesesubjects(32,33,36),2trialsinhyperinsulinemicsubjects(16,23),1trialinthosewhowereimpairedglucose-tolerant(22),and1trialinsubjectswithtypeIVhyperlipoproteinaemia(HLP)(15).Backgrounddietswere42-55%carbohydrate,25-38%fat,and13-20%protein.Thecarbohydratecomparatorschoosestarchin13trials(15,16,21,23-25,27-30,32,36),glucosein6trials(22,31,33-35),sucrosein3trials(17,18,26),andmixedcarbohydratesintwotrials(19,20).Fourtrialsusedfructoseincrystalline(16,18,20,21),5trialsinliquid(19,32-35),and15trialsinmixedform(15,17,22-31).ThereportedmeanbaselineserumTCrangedfrom170to230.8mg/dl,LDL-Crangedfrom90.7to157mg/dl,andHDL-Crangedfrom35.1to57.1mg/dl.Nineteentrialsreportedthefructoseintakeamongbackgrounddietwasnotdifferentbetweenthefructoseandcontrolgroups,inwhich15trialsreportedthebackgroundfructoseintakeaccountfor≤3%oftotalenergy(9to24g)(15-23,29,32,33,35),while4trialsdidnotreporttheproportionofit(24,25,26,34).Fourtrialsusedbackgroundfructose≤3%(3.2to18g)oftotalenergyinthecontrolgroups,butputtotalfructoseintoconsiderationinthefructosegroup(27,28,30-31).Onlyonetrialreportedlessthan20g(4.3%oftotalenergy)fructosewasconsumedamongbasaldiet(36).Thebaselinevalueswerenotprovidedin5trials(19,22,23).Themedianfructosedoseintheavailabletrialsincludedinourmeta-analysiswas79.25g/d(range:30-182g/d),andthedurationvariedfrom2to26weeThequalityscoresofeachstudyrangedfrom6to9.Fifteentrialswereclassifiedashighquality(MQS≥8),and8trialswereoflowquality(17,19,26,30,32-35).Onlythreetrialswereblinded,onesingle-blinded(34)and2double-blinded(29,35).Eighttrials(19,21,24,26-30)receivedindustryfunding.Threestudieswithfourtrials(15,16,22)didnotreportanyinformationaboutfinancialconflictsofinterest.EffectoffructoseoncholesterolTotalcholesterol.Twenty-twotrials(16-34,36)reportedthevalueofTC,andthepooledestimatewas2.47mg/dL(95%CI:-3.04,7.98;P=0.38)withoutstatisticallyheterogeneity(heterogeneityChi2=28.14,I2=25%,P=0.14)(Fig.1).Theresidualsourcesofheterogeneitywereinvestigatedbymeta-regressionmodels.Univariatemeta-regressionshowedthatthefructosedosewaspositivelyrelatedtoTC,evenafteradjustedforstudydurationandhealthstatus(regressioncoefficient=0.18;95%CI:0.06,0.31,P=0.008)(Table2).Thedose-responserelationbetweenfructoseconsumptionandTClargelyexplainedtheresidualheterogeneityoftheeffect.Subsequently,westratifiedfructosedose≤60,>60to100,and>100asmoderate,high,andveryhigh,respectively,accordingtoCandianDiabetesAssociationandreferencerangesforfructose(9,37,38).FructosecouldsignificantlyincreaseTCby12.97mg/dL(95%CI:4.66,21.29;P=0.002)whenfructoseintakeswere>100g/dbuthadnoeffectonTCiffructosewasgivenlowerthan100g.Predefinedsubgroupanalyseswereconductedbystudycharacteristics(SupplementalTable1).Sensitivityanalysesaccordingtopossiblecorrelationcoefficients(0.25and0.75)andsystematicallyremovalofeachindividualtrialdidnotaltertheoverallanalysisandanalysesstratifiedbydose.LDLcholesterol.ThemeanchangeforLDLcholesterolinnineteentrials(15,16,18,20,22,23,25-35)was3.76mg/dL(95%CI:-1.07,8.6;P=0.13)withoutstatisticallyheterogeneity(heterogeneityChi2=19.85,I2=9%,P=0.34)(Fig.2).Theresidualsourcesofheterogeneitywereinvestigatedbymeta-regressionmodels.Univariatemeta-regressionshowedthatthefructosedosewaspositivelyrelatedtoLDL-C,evenafteradjustedforcomparators,studydurationandhealthstatus(regressioncoefficient=0.15;95%CI:0.03,0.28,P=0.02)(Table2).Thedose-responserelationbetweenfructoseconsumptionandLDL-Clargelyexplainedtheresidualheterogeneityoftheeffect.WestratifiedfructosedoseaccordingtoCDAandreferencerangesforfructose(9,37,38).Fructoseintake>100g/dcouldsignificantlyincreaseLDL-Cby11.59mg/dL(95%CI:4.39,18.78;P=0.002).Predefinedsubgroupanalyseswereconductedbyotherstudycharacteristics(SupplementalTable1).Sensitivityanalysesacrosspossiblecorrelationcoefficients(0.25and0.75)didnotaltertheoverallanalysisandanalysesstratifiedbydose.TheremovalofCybulskaetalresultedinasignificantLDL-C-raisingeffectintheoverallanalysis(P=0.03).HDLcholesterol.TheresultofHDLcholesterolwascalculatedbasedon24trials(15-36),themeandifferencewas-0.56mg/dL(95%CI:-2.05,0.93;P=0.46)withoutheterogeneity(heterogeneityChi2=21.85,I2=0%,P=0.53)(Fig.3).Meta-regressionanalysisdidnotshowsignificanteffectmodifierofHDL-C.Predefinedsubgroupanalyseswereconductedbystudycharacteristics(SupplementalTable1).Sensitivityanalysesaccordingtopossiblecorrelationcoefficients(0.25and0.75)andsystematicallyremovalofeachindividualtrialdidnotaltertheoverallanalysis.PublicationbiasFunnelplotsandEgger’stestindicatednosignificantpublicationbiasinthemeta-analysesofTC,LDLcholesterol,andHDLcholesterol(TCEgger’stest:P=0.881;LDLcholesterolEgger’stest:P=0.815;HDLcholesterolEgger’stest:P=0.484)(SupplementalFigs.2-4).DISCUSSIONThismeta-analysisof24controlledfeedingtrialswith477subjectsfoundnoeffectonTC,LDL-CandHDL-Cwhenfructosewassubstitutedforothercarbohydrates.Residualheterogeneitywasdetectedbymeta-regressionforthisoutcomethatfructosedosewaspositivelycorrelatedwiththeeffectsizesofTCandLDL-C.Thepresentmeta-analysisisconsistentwithaprospective2-yeartrialonchroniceffectoffructosefromTurkusugarstudiesXI,whichdidnotreportanychangeincholesterolforthoseindividualswhoconsumedmorethan100gfructose/d(39).Aeberlietalreportedanotherprospective,randomized,3-weekcontrolledcrossovertrialinwhichhealthyyoungmenwerefed80g/dfreefructose,andfoundasignificantatherogenicLDLsubclassdistribution(4034gcombinedfructoseconsumedamongbasalfoodsinthisstudy,whichmeantsubjectsconsumedfructoseover110g/d.Themediandoseoffructoseavailableinourmeta-analysiswas≈79.25g/d,itwashigherthan90thpercentile(78g/d)andlowerthan95thpercentile(87g/d)intheUnitedStates,reportedbytheNationalandHealthandNutritionExaminationSurveyIII(41).Asforsubjectswithdiabeticmellitus,Sievenpiperetaldidnotreportcholesterol-raisingeffectifthefructosedosewas>60g/d(median:97.5g/d)intheirmeta-analysis(42TheresultsofsubgroupanalysesshowedthattheeffectsoffructoseintakeonTCandLDL-Cweresignificantasthefructosedose>100g/d.Anintakeof100g/disapproximatelyequalto400kcal/dor20%ofenergyintakeforasedentarypersonwithanenergyrequirementof2000kcal/d.Thedosesforcholesterol-raisingeffectaccountforlessthan10percentofintakeinmalesandfemalesaged19to22years,thegroupwiththehighestlevelofexposureintheUnitedStates(41).AnotherstudyfoundthattheupperquintileofAmericansconsumemorethan110gfructosedailyasaddedsugarorashigh-fructosecornsyrup(43).Althoughasmallnumberofpeopleconsumefructoseatveryhighdose,itisnecessarytoadvisethemtochangetheirlifestyle.Thedose-dependenteffectontriglyceridewasalsoreportedinarecentmeta-analysisthatconcludedthesamedosethresholdof100g/dforatriglyceride-increasingeffectoffructoseonfastingtriglyceridelevelinadulthumans(38).Forhealthysubjectswhoconsumed150goffructose/day,endogenouscholesterolsynthesisandthefatcontentofvisceraandliverhavebeenshowntoincrease(44).Allevidenceshaveprovedthatfructoseisproposedtohaveadverseeffectsatveryhighorexcessivedoses.Themechanismofthecholesterolincreasebyfructosemightbeduetoincreasedlevelsofadvancedglycationendproducts,whichcausedamagetoLDLandmakeitpoorlyrecognizedbylipoproteinreceptorsandscavengerreceptors(45).Furthermore,excessexposuretofructosecandamagethefunctionofadipocytesandmayreducetherecyclingofcholesterolextractedfromserumLDL.StudieshaveshownthatelevateduricacidmightcontributetoLDL-Cincreases,andthiseffectcanbereducedbyallopurinol(46).BasedonthecompositionofaddedsugarsintheUnitedStateswherethefructose:glucoseratioiscloseto0.43,andtheNHANES1999–2004estimates(41),theincreaseoffructoseconsumptionisalwaysaccompaniedwithanincreaseintotalenergyintake.Personsconsuming>100g/dofsugarsarepotentiallyeatinginexcessoftheirenergyrequirement(47),andthenoverweightandobesitycouldresult.Sowecannotsuggestthatitissafetoonlylimitfructoseto<100g/dincoronaryheartdiseasemanagementandprevention.Itmayneedtotakeintoaccounttheothercomponentsoffoodsthataccompanythefructose.ThisdosethresholdeffectsonTGandLDL-Ccanonlyhelpbetterinformnutritionalguidanceandavoidinappropriatemarketingofcarbohydrates.Ourmeta-analysisdidnotshowsignificanteffectoffructoseonHDL-C.However,Perez-Pozoetal(46)reportedasignificantHDL-C-lowingeffectin74adultmenfedwith200gfructose/dinarandomized,2-weekcrossovertrial,suggestingthatexcessivefructosedoseintakecanalsoaffectHDL-C.FurthertrialsareneededtofindthethresholdoffructoseonHDL-C.Thereareseverallimitationstoourwork.First,manytrialshadarelativelysmallsamplesize,andmostofthemwerefundedbyindustrywhichcanaffectthequalityofstudies.Second,thechangeoffructoseinthebackgrounddietcanaffectthepracticalutilityoftheoutcomesofmeta-analyses.However,mostoftrialsusedthebackgrounddietwith≤3%oftotalenergyderivedfromfructose(15-23,27-33,35),otherstrialsdidnotreporttheproportionoffructoseinthebackground(24,25,26,34).Itwashardtomakesurethedoseofbackgroundfructoseineverytrial.Third,thedataprovidedbyReiseretal(23)mustbeinterpretedwithcaution.Althoughthisstudymetallofourinclusioncriteria,theychoosealowP:S(polyunsaturated:saturated)rateofthefatasthebackgrounddiet,whichmightchangethemetabolismoffructoseasdietshighinsaturatedfattyacidscanenhanceintestinalfructoseabsorption(48).Fourth,someofincludedtrialslackteststatistics,baselinevaluesandSDs.WeovercametheseproblemsaccordingtothemethodsproposedbyCochraneHandbookforSystematicReviewsofInterventions.Finally,itisdifficulttodifferentiateeffectsofothermodifiers,suchasexerciseandage,fromthoseincludedtrials.Thesefactorscanalsoinfluencethefinalresult.Fructosecanindeedbemetabolizedduringexercise,andtherateofmetabolismisdifferentbetweenexerciseandsedentarylifestyle.Mostofparticipantswererequestedtofollowadesignedregimentathome,butitisnoteasytomaintaintheactivityintensity.Ontheplussize,theageofparticipantsinourmeta-analysisrangedfrom18to72yearsold.Evidencefromanimalexperimentsshowsthatfructoseabsorptionmayaffectedbyage,asolderratsshoweddecreasedfructoseabsorption(49).However,nohumantrialhasbeendonetoassessthedifferenceinfructoseeffectamongdifferentagegroups.Therefore,furtherstudiesshouldattempttolimitorisolatethedegreeofheterogeneitypresentinthestudypopulationtobetterassesstheeffectofage.Inconclusion,ourmeta-analysisshowsthatfructoseusedasasweetenerinisocaloricexchangeforothercarbohydrateshassignificantincreasingeffectsonTCandLDL-Cinindividualswithveryhighfructose(>100g).Thiseffectseemsnottobedose-dependentwhenfructoseisgivenatmoderateorhighdoseoffructose(<100g).Furtherstudiesshouldconcentrateonlarger,longerandhigher-qualityhumancontrolledfeedingtrials,whichprovideabetterassessmentoftheeffectoffructoseoncholesterol.AcknowledgementsTaoAn,RongChengZhangandJianZhangdesignedtheresearch;TaoAn,RongChengZhang,YuHuiZhangandJianZhangpreformedtheresearch;TaoAnandRongChengZhangsummarizedthedataandhadprimaryresponsibilityfortheaccuracyoftheanalysis;RongChengZhangwrotethemanuscript.Alltheauthorshadfullaccesstothedata.Noneoftheauthorsdeclaredaconflictofinterest.LiteratureCitedRogerVL,GoAS,Lloyd-JonesDM,etal.Heartdiseaseandstrokestatistics-2012update:areportfromAmericanHeartAssociation.Circulation2012;125:e2-220.YusufS,HawkenS,OunpuuS,etal.Effectofpotentiallymodifiableriskfactorsassociatedwithmyocardialinfarctionin52countries(theINTERHEARTstudy):case-controlstudy.Lancet2004;364:937-52.GibneyM,Sigman-GrantM,StantonJLJr,KeastDR.Consumptionofsugars.AmJClinNutr1995;62(1Suppl):178S-93S.JenkinsDJ,WoleverTM,TaylorRH,etal.Glycemicindexoffoods:aphysiologicbasisforcarbohydrateexchange.AmJClinNutr1981;34:362-6.TappyL,LêKA.MetaboliceffectsoffructoseandtheworldwideincreaseinDhingraR,SullivanL,JacquesPF,WangTJ,FoxCS,MeigsJB,D'AgostinoRB,GazianoJM,VasanRS.Softdrinkconsumptionandriskofdevelopingcardiometabolicriskfactorsandthemetabolicsyndromeinmiddle-agedadultsinthecommunity.Circulation2007;116:480-8.StanhopeKL,HavelPJ.Fructoseconsumption:considerationsforfutureresearchonitseffectsonadiposedistribution,lipidmetabolism,andinsulinsensitivityinhumans.JNutr2009;139:1236S-41S.DGAG2010ReportoftheDietaryGuidelinesAdvisoryCommittee(DGAC)onthedietaryguidelinesforAmerican,2010./dgas2010-dgacreport.htmCanadianDiabetesAssociation2008clinicalpracticeguidelinesforthepreventionandmanagementofdiabetesin